Food problems coexist with anxiety and depression and represent an increasing concern of developed countries (Garrow, 1991; Kuczmarski et al., 1994). As for the majority of neurophychiatric pathologies, the combination of the influence of environmental factors and a genetic predisposition seems to be responsible for these behavioral deficiencies (Fairburn et al., 1998; Lilenfeld et al., 1998; Barsh et al., 2000). The mothers of 75% of anorexic women suffer from depression or are alcoholics one year before the expression of the symptoms of their child. The anorexic syndrome is also detected more frequently in one and the same family than in the general population without any gene associated with this pathology having been identified. Bulimic behaviors, frequently concomitant with anorexia in the same individual, are characterized by impulsive and repeated phases of ingestion of an elevated amount of food.
Bulimia is thus classified among behaviors associated with addiction (international definitions of psychiatry, DSM). Food can be considered as a reward the obtention of which is based on will (wanting: appetite/incentive motivation) and is motivated by a component associated with hedonism (liking: pleasure/palatability) (Hoebel, 1997; Salamone et al., 1997; Stratford and Kelley, 1997; Stratford and Kelley, 1999). The excess or the absence of ingesting food is limited not only to metabolic and/or endocrinal deficiencies, but also depends on stress (Donohoe, 1984; Morley et al., 1983; Vergoni and Bertoline, 2000), on anxiety (Godart et al., 2000) and on depression (Viesselman and Roig, 1985; Casper, 1998).
The hypothalamus, the amygdala and the hippocampus are involved in the regulation of the consumption of food. Moreover, the activity of the neurons of the nucleus accumbens is modified during the anticipation or after the obtention of a classic reward such as food or drugs of abuse (Di Chiara, 1995; Hoebel, 1997; Koob and Nestler, 1997; Salamone et al., 1997).
Even though the emergence of discoveries shows the involvement of numerous peptides in the regulation of food behaviors (leptine, orexines, hypocretines, CART, NPY, POMC, CRH, TRH), the influence of classic neuromediators such as serotonin (5-HT) and dopamine (DA) cannot be avoided. GABA and glutamate should also be considered (Taber and Fibiger, 1997; Kelley and Swanson, 1997; Stratford and Kelley, 1997; Stratford et al., 1998).
Dopaminergic systems of the nucleus accumbens are involved in the anticipation of a reward (drugs of abuse, food). A chronic administration of clozapine, antagonist of the receptors of DA, induces a hyperphagia (Ackerman and Nolan, 1998; Allison et al., 1999). Cocaine and amphetamine, known for increasing the transmission of DA, are anorexigenic (Foltin and Evans, 1999).
Nevertheless, the serotoninergic systems remain an inevitable link that controls ingestion of food (Barnes and Sharp, 1999) due to the use of fenfluramine, inhibitor of the capture of serotonin in obese patients (Guy—B. Grand, 1995).
In sum, deficiencies of the combinations of interactions between factors of the environment (stress) and genetic factors (genes coding for receptors present in the brain) appear to be responsible for behavioral problems such as bulimia, anorexia or the addiction to drugs of abuse. These pathologies and, in a more evident manner, bulimia are considered today to be an addictive behavior.
On the neurobiological level, the state of our knowledge favors the combined intervention of several neuronal systems for regulating food behavior. The best known are the serotoninergic systems that express the cerebral messenger (neuromediator), that is 5-HT. The cerebral areas where their actions are manifested are primarily the hypothalamus, the amygdala and the nucleus accumbens.
The exact relationship between the effects of stress and 5-HT is rendered complex by the reciprocal influence between activities of the serotoninergic systems and the hypothalamo-pituitary axis (F. Chaouloff, 2000). On the other hand, application of stress brings about increases in the serotoninergic transmission.
Stress causes elevations in serotoninergic transmission. The experimental paradigms in which stresses associated with a conditioned fear bring about an increase in the metabolism and release of 5-HT in the median pre-frontal cortex (Adell et al., 1997; Inoue et al., 1994), the nucleus accumbens (Inoue et al., 1994; Ge et al., 1997), the amygdala (Amat et al., 1998) and the dorsal hippocampus (Ge et al., 1997; Joseph and Kennett, 1983). In particular, the stress of constraint (forced immobilization) increases renewal of 5-HT in the hypothalamus and the amygdala of the rat and mouse (Konstandi et al., 2000). In the same manner, the action of corticotropin-releasing hormone or factor (CRF) on the serotoninergic neurons of the corticomesolimbic system might be able to modify the rates of 5-HT (Lowry et al., 2000; Price and Lucki, 2001). In addition, alterations of the functioning of the receptors of the glucocorticoids produce variations in the concentration of 5-HT in the nucleus accumbens (Sillaber et al., 1998). Moreover, the repeated injection of corticosterone increases the activation of the neurons of the hippocampus (CA1) induced by an agonist of the 5-HT4 receptor (Zahorodna et al., 2000). Finally, numerous studies suppose that CRF is responsible for the anorexigenic effect of stress. In particular, the intracerebroventricular injection of CRF induces a diminution of ingestion of food in the mouse (Momose et al., 1999).
Serotonin inhibits ingestion of food. The pharmacological approaches combined with the strategies of transgenesis indicate that the receptors 5-HT1A/1B and 5-HT2A/2C are involved in regulating ingestion of food and, moreover, of stress (Bonasera and Tecot, 2000; Bouwknecht et al., 2001; Dourish et al., 1986; Heisler et al., 1998; Lucas et al., 1998; Samanin and Garattini, 1996). Anorexia associated with stress is assumed to result from the increase in the activity of serotoninergic neurons. Numerous studies attribute the anorexigenic effect of fenfluramine to the activation of the 5-HT1B receptor whereas that of the 5-HT1A (autoreceptor), inhibiting the release of 5-HT, induces an elevation of ingestion of food. The insensitivity of mice lacking receptor 5-HT1B in the injection of fenfluramine confirms its involvement in regulating ingestion of food (Lucas et al., 1998). The receptors 5-HT2C also intervene in the consumption of food because the mice deprived of it are obese (Heisler et al., 1998). Leptine is known to reduce ingestion of food, but it is not associated with this obesity (Nonogaki et al., 1998).
A recent study shows that the 5-HT2C receptors are also responsible for the anorexigenic effect of fenfluramine (Vickers et al., 2001). Finally, administration of tropisetrone, antagonist of the receptors 5-HT3 and 5-HT4, increase ingestion of food of a diet modified by a single amino acid (Erecius et al., 1996). However, this effect has been attributed to the 5-HT3 receptor (Jiang and Gietzen, 1994). Consequently, no data is currently available concerning the contribution of the receptor 5-HT4 in ingestion of food.
In sum, the current hypothesis for explaining that stress reduces ingestion of food is based on two series of parallel studies. The first one describes that stress increases the activity of the hypothalamo-pituitary axis (stress axis) and the serotoninergic neurons. Furthermore, hyperactivity of the hypothalamo-pituitary axis causes an increase in the rates of hormones such as CRF, urocortin and, in the final stage, of corticosterone. The second series of analyses shows that the hormones of the stress axis and 5-HT inhibit the taking of food.
As a consequence, numerous people propose the following sequence of events:
Application of stress   brain  anorex hypothalamo-pituitaryand/or? serotoninergic neurons
The set of the receptors of 5-HT are coupled with the G proteins with the exception of the receptor 5-HT3, that is an ionic channel (Saudou and Hen, 1994). The receptors 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F are negatively coupled to adenylate cyclase and have a strong affinity for 5-HT. Activation of receptors 5-HT2 stimulates activity of phospholipase C (5-HT2A/2C). The other receptors of 5-HT are positively coupled to adenylate cyclase and include 5-HT4, 5-HTdrol in the vinegar fly, and the receptors 5-HT6 and 5-HT7 in mammals. The receptor 5-HT4 was described for the first time in the colliculi (Dumuis et al., 1988) and its stimulation brings about an elevation of the rates of AMPc in the hippocampus, the cerebral cortex, the atrium and the esophagus. In humans, nine subtypes of 5-HT4 receptors named 5-HT4A, 5-HT4B, 5-HT4C, 5-HT4D, 5-HT4E, 5-HT4F, 5-HT4G, 5-HT4H and 5-HT4N differ by their C-terminal end point (Bockaert et al., 2003, in the press, for review). The system for the transduction of receptors 5-HT5A is positively associated with adenylate cyclase. That of 5-HT5B has not yet been identified.
Functional influences of the 5-HT4 receptors have been studied intensively in the gastrointestinal tract, but little data is available about their contributions in the brain. Of the set of the structures of the encephalon in rodents and in man, the greatest densities of the 5-HT4 receptor are detected in the limbic system (Waeber et al., 1994). In particular, its concentration is three times greater in the shell than in the core of the nucleus accumbens (Compan et al., 1996). In the brain of rodents their rate varies during development and does not attain their adult level until the 21st day after birth (Waeber et al., 1994). In the encephalon of the rat the rates of mRNA's coding for the 5-HT4 receptor are greatest in the olfactory system, the striatum, the nucleus accumbens, the habenula and the hippocampus (Gerald et al., 1995; Ulmer et al., 1996; Vilaro et al., 1996).
The agonists of 5-HT4 receptors cause a reduction in the deficiencies of memorization and improve learning by setting transmission of acetylcholine in motion (J. Bockaert et al., 1998). It is tempting to suppose that the 5-HT4 receptor can participate in the neuronal mechanisms of the nucleus accumbens associated with the learning of food. Four pharmacological studies have demonstrated a low contribution of the 5-HT4 receptor in the “anxiety” state of the rat and of the mouse (Cheng et al., 1994; Silvesre et al., 1996; Kennett et al., 1997; Costall and Naylor, 1997). Inhibition of the 5-HT4 receptor brings about a decrease in locomotive activity in the rat under basal conditions (Fontana et al., 1997), in the young mouse 20 to 27 days old (Semenova and Ticku, 1992) and can attenuate cocaine-induced hyperlocomotion (McMahon and Cunningham, 1999).
In the striatum, serotoninergic control of the rates of extracellular DA by the activation of the 5-HT4 receptor is simultaneously described as exciting or inhibiting (Bonhomme et al., 1995; Steward et al., 1996; Deurwaerdere et al., 1997).
Finally, stimulation of the 5-HT4 receptor brings about a closing of the ionic channels of potassium (Bockaert ea, 1998), which is capable of maintaining the excitability of neurons and augmenting the release of neuromediators. In agreement with this data, stimulation of the 5-HT4 receptors leads to an increase in the rates of extracellular 5-HT in the hippocampus.
In sum, at the neurobiological level, 5-HT4 receptors are known to intervene in learning and memory. The possible contribution in motor behavior and the anxiety state is currently described as moderate and has been little studied. A single study indicates that this receptor can intervene in the effect of cocaine on locomotive activity.
Furthermore, WO 97/29739 discloses use of antagonists of the 5-HT4 receptor for preparation of a drug intended to avoid, alleviate, suppress or master the gastrointestinal effects caused by a selective inhibitor of the re-assimilation of serotonin.
WO 02/11766 discloses use of antagonists of the 5-HT4 receptor in the prophylaxis or treatment of certain cardiovascular conditions.